There is accumulating evidence for an increasing incidence of chronic diseases in the human population. These diseases are generally complex, with aspects of genetic control interacting with environmental stressors to trigger the symptoms of the diseases. Additionally, many of these diseases clearly are manifested by chronic inflammation that contributes to loss of function of cells, tissues, or organs resulting in disease outcomes. It is also becoming more apparent in the post-genomic, "personalized medicine" era that these diseases are observed in a subset of the population that present with "at risk" genotypes translating into phenotypic expression of disease. In this regard, the chronic inflammation occurring in inflammatory bowel disease and rheumatoid arthritis have many similarities to the chronic immunoinflammatory response in the oral cavity that destroys the soft and hard tissues of the periodontium (i.e. periodontitis). Reactive oxygen species (ROS) are generated during inflammation, particularly in regions of microbial challenge as an important protective mechanism for the host. However, chronic production of the toxic reactive materials presents a situation where tissue damage and loss of function can occur related to a chronic inflammatory response. The project will focus on evaluating molecular aspects of inflammatory periodontal disease using a "chronic model" elicited by local administration of Trinitrobenzene sulfonic acid (TNBS) that elicits a localized chronic inflammatory response that undermines the integrity of the epithelium, and upregulates ROS, and a more "acute model" of ligature-induced periodontitis.. The objectives of this proposal will be to test the hypothesis that treatment of mouse models of chronic and acute inflammatory periodontitis with agents that regulate ROS production and function will decrease local inflammation and alveolar bone loss. The approach will be to treat mice with distinct antioxidants, a cysteine prodrug 2-(RS)-n-propylthiazolidine- 4(R)-carboxylic acid (PTCA) and a glutathione (GSH) prodrug s-adenosylmethionine (SAMe), to interfere with molecular events elicited by ROS produced during inflammatory periodontal disease. These studies will use wild-type mice (Aim 1) and mice with a deficiency in superoxide dismutase (SOD1) as a major intrinsic molecule that protects against ROS damage. The implementation of the TNBS model of chronic inflammatory bone resorption and the ligature-model of acute inflammatory bone loss will enable comparison of contribution of ROS to osteoimmunological interactions in the oral cavity. We would predict that the experimental designs will demonstrate an important role for ROS in alveolar bone resorption, and will enable identification of various gingival gene products that contribute to the local milieu reflecting this tissue destructive process. These findings should be exacerbated in the SOD1 knockout mice. The therapeutic strategies will also lay the ground work for more targeted control of ROS production as related to molecular pathways of host cell activation in the gingiva, and osteoimmunologic linkages that result in alveolar bone resorption. The results will enable extended studies through R01 applications that will use these models to examine additional extrinsic antioxidants for controlling this disease, as well as studies of the contribution of other intrinsic antioxidant components (ie. glutathione, GST, metallothionein) to establishing homeostasis in the periodontium. PUBLIC HEALTH RELEVANCE: Chronic inflammation of the oral cavity destroys the soft and hard tissues of the periodontium (ie. periodontitis) and causes tooth loss. These pathological changes can result from dysregulated production of reactive oxygen species. Specific aims for this proposal will examine targeted antioxidant therapies using mouse models of oral disease as a potential strategy for adjunctive management of human periodontitis.